Everyone, we're back. Really happy to have the Jade Biosciences team here with us for the next fireside, Tom Frohlich, CEO, Andrew King, President of R&D, CSO, IgAN extraordinaire. Maybe I'll kick it over to Tom to give us a quick overview of the company, and then we'll get into the Q&A.
Thanks so much, Alex, and thanks for hosting us and all the support from Stifel in the conference and beyond. Jade, we're a company focused on developing best-in-class assets across a number of different autoimmune diseases. We have three assets that we've licensed from Paragon, which I'm sure many people are familiar with. They're super high-quality protein engineers focused on developing high-affinity binding antibodies with long half-life to develop best-in-class therapeutics. We have three assets. Our lead program is JADE101, which is anti-APRIL, focused on IgAN initially. We think it's a best-in-class profile with a possibility of having deepest levels of IgA reduction to maximize clinical activity available to the mechanism, and to be able to do that in a very convenient format with a Q12-week maintenance dosing for patients.
That program's currently in a phase II trial with data expected in 2027, and we're moving exceptionally quickly to initiate a phase III trial, which we're anticipating dosing the first patient in the first half of 2027. We also have JADE201, which is an anti-BAFF Receptor antibody, really applicability across a number of different autoimmune disease, anything that's B-cell mediated. That program is currently in a phase I rheumatoid arthritis trial, moving towards data next year as well in 2027. Broad indication potential. We're following the footsteps of ianalumab, although JADE201 has a longer half-life, so we can capture better clinical activity with more convenient dosing for patients as well. JADE301, recently disclosed, very exciting program. It's an anti-interferon beta, going after dermatomyositis, an area of large unmet need.
We're currently tracking towards initiating that program, dosing the first healthy volunteer this year in a phase I study with data next year in 2027. That program is following in the footsteps of another anti-interferon beta in dermatomyositis called dazukibart, which is at Pfizer. We're aiming to have subcutaneous dosing where dazukibart is IV and really capture the clinical activity that we've seen with interferon beta, which is really the best results in terms of total improvement score on neuromuscular aspects, but also on the skin. Super exciting program. All that's underpinned by a strong financial position and a really high-quality team that can move these programs forward.
Great overview. We have seen now two of the two-year phase III data sets out of the first-gen APRIL, BAFF/APRILs from both Otsuka with sibeprenlimab and atacicept from Vera. Both of them, long story short, stabilize eGFR at two years. From that perspective, where is the unmet need in IgAN as we kind of look at those data sets?
Yeah. You introduced Andrew as IgAN extraordinaire, so Andrew, why don't you take that one?
Yeah. It has been really, truly remarkable to see the evolution of the anti-APRIL response in IgAN over the last five or so years. This eGFR stabilization we have now seen that you referenced from both sibeprenlimab and atacicept in phase III is truly transforming for the trajectory of these young IgAN patients that would typically face high lifetime risk of progressing to end-stage kidney disease requiring dialysis or transplantation. We do think that that really sets the bar and is likely the best you can achieve in IgAN is that eGFR stabilization, since decreased eGFR in chronic kidney disease and in IgAN specifically is generally thought to be a result of a loss of nephron number, which won't be restored by a therapy like this. So stabilization is the best you can hope for.
We hope to be able to replicate that with JADE101, that full disease-modifying benefit manifested through eGFR stabilization. But we do think there are important opportunities to differentiate in this patient population. Firstly, as I mentioned, these are young adults when they are diagnosed in their 20s and 30s, so they need lifelong therapy, potentially for decades. So we do think that convenience and reducing the patient burden is going to be really important in IgAN to give them more freedom from their autoimmune disease, and that fear of progressing to end-stage kidney disease. With JADE101, it has been designed for convenient infrequent sub-Q injections to reduce the patient burden, provide better convenience, and more freedom for these young, otherwise healthy IgAN patients.
We also think there's opportunity, according to the guidelines, to really deliver agents that not only stabilize eGFR, which is great long term, but is difficult to treat towards because you need long-term follow-up to really understand the trajectory of eGFR. The guidelines are really focusing on these strict proteinuria targets, driving patients back below 0.5 g per day, preferably back to within the normal range of 0.3 g per day, which gives you the greatest confidence that that long-term eGFR and the long-term outcomes will be favorable for these patients without having to track eGFR over time.
We do think there's some opportunity to differentiate on efficacy with JADE101 being a highly potent femtomolar inhibitor APRIL, and being administered with a loading dose or induction dose strategy with the goal to drive IgA down as quickly as possible and as deeply as possible to try and bring earlier benefits in terms of proteinuria reduction and higher rates of achieving those remission-like targets, which would be a great profile to combine with the convenient infrequent dosing schedule.
Yeah. With that context, I guess, can you talk through the phase I data and sort of where those data sort of fit into how you're thinking about that product profile?
Yeah, the phase I data is particularly informative in the setting of an anti-APRIL therapy in IgAN because it's so translationally rich with biomarkers that are ultimately predictive of clinical efficacy in IgAN. IgAN is a disease driven by IgA-containing immune complexes. The really rich responses you get with IgA reduction in healthy volunteers, which is highly consistent with the IgA reduction you ultimately see in IgAN patients with these agents and is predictive of clinical benefit. The early IgA reductions observed at eight weeks with an anti-APRIL have a high association with the proteinuria reductions you ultimately see at week 36. We think that's a particularly important endpoint to anchor on in the phase I study.
And what we observed with JADE101, consistent with our goal of delivering these rapid and deep IgA reductions early to produce the best benefit on proteinuria, was at the 700 mg induction dose, we saw a 70% reduction in IgA, which is numerically greater than has been observed with single doses of the first-generation agents, which were really bottoming out in the mid 50% reduction from baseline and required repeat dosing over time to get down to those larger reductions in IgA. We do think that particular endpoint from the phase I study is highly encouraging about the profile of JADE101, and in our view, highly de-risking.
Yeah.
That we won't be able to deliver the full disease-modifying benefit of IgA reduction. Also, the duration of the IgA reduction is particularly important from that phase I study. At that induction dose, it was fully maintained through 12 weeks post single dose. That gives us high confidence when we combine that induction strategy with our maintenance plan, initiating a single 350 mg injection at week four, in the setting of fully saturated TMDD, to further drive down and maintain those IgA reductions. We can deliver a Q12-week maintenance dose of a single injection, so only four injections per year, in this young patient population delivering the full IgA lowering benefit of the MOA is a really exciting profile for us.
As we think about phase II clinical data in IgAN patients, what do you think this 70% IgA reduction could translate into? I think, do we expect to see deeper absolute reductions in proteinuria? And then maybe, from a clinical remission perspective, can you also put into context what the bar is that we've seen from these first gens? We don't have a lot of clinical remission data out there, but can you put some numbers to what we've seen so far?
Yeah. What we've seen with the first-gen agents is that as IgA continues to deepen over time, proteinuria continues to go down further over time. We feel like if we can bring our IgA reductions forward with this potent molecule induction strategy, we can produce that proteinuria benefit earlier.
That would be quantitatively larger reductions in proteinuria, but as you highlight, probably more importantly, is more patients achieving targets in the KDIGO guidelines. Those targets are 0.5 g per day, and you do not need an additional therapy, preferably below 0.3 g back to within the normal range. Different sponsors have reported these remission data slightly differently, so it is a little bit challenging to compare head-to-head. Probably the richest data so far is from sibeprenlimab.
Their phase III study, which is now complete, where they report about 35% of participants achieve proteinuria below 0.5 g per day. So that does leave 65% of the high-risk population studied in phase III eligible, and per guidelines, requiring an additional treatment to get to those threshold targets. There is significant room to move if you can deliver earlier and greater proteinuria reduction to drive a greater proportion of patients to below those thresholds. We think that is going to be an important battle commercially.
Yeah.
If you can have the agent that can deliver the largest, earliest reduction of proteinuria, highest rates of remission, and combine that with a convenient dosing schedule. We think that is going to be a great profile for IgAN patients.
Looking ahead to next year, you have your phase II that is ongoing, looking at every eight-week and every 12-week dosing. You have some flexibility around when you could disclose data. I guess what quantum of data do you want to have, and what kind of follow-up would make sense for disclosure in your view?
Yeah. It is an ongoing study, so we do have 15 patients per arm.
Yeah.
30 patients total. We want to have something that is fairly robust that we.
Yeah.
Really can characterize as the drug. We want to see that we are replicating some of the biomarker data we saw at the higher doses in the phase I. We want to see that replicating in patients. Then as Andrew pointed out, obviously proteinuria data is going to be.
Yeah.
Exceptionally important. We will look really closely at that. We have not guided to exactly what number that will be.
Yeah.
It's going to be one of those we'll know it when we see it. I think a good reference point is looking at some of the earlier agents like povetacicept. They had a handful of patients out to 36 weeks, and then a bigger number out to 12 and 24 weeks. We'll report out that data next year when we think it's a meaningful amount for characterizing the drug. We do have to caveat, it is a small number of patients.
Yeah.
It really is there just to confirm that we're seeing the same reductions in biomarkers in patients as we saw in healthy volunteers. We want to be really clear, we're not waiting for that data.
Yeah.
To initiate the phase III. We want to move forward exceptionally quickly, and initiate that data in the first half of next year.
That's a good transition towards the pivotal study. I guess, where are you currently in conversations with FDA post this spring NKF meeting, where does that stand today?
Yeah. Andrew, you want to talk about that?
Yeah. We're really encouraged about the evolution of the phase III trial design in IgAN, given the evolving therapy being approved with multiple agents, particularly in the U.S., now approved for the treatment of IgAN. The FDA recognized this evolution and requested the NKF set up a workshop that included regulators, IgAN KOLs, and investigators, sponsors, as well as a strong voice from IgAN patients to understand what a trial design looks like now in the setting of multiple approved therapies. The main focus of that conversation was the recognition that two-year placebo-controlled trials are going to become increasingly challenging and likely unnecessary given the large treatment effects we've seen with these disease-modifying agents, and the inevitable decline in eGFR you do see on placebo being unacceptable given the availability of these new therapies. Following that, the FDA was actively engaged.
They provided additional feedback to sponsors and have made commentary publicly at scientific conferences, all in support of the potential of a one-year eGFR endpoint being sufficient for full traditional approval. That makes the study design much more efficient and much more attractive to patients, a shorter duration of placebo control, with the potential for long-term open label access to JADE101 following that 12-month eGFR endpoint. So we're designing a study consistent with that new guidance from the FDA around a 12-month placebo-controlled trial, with proteinuria and eGFR at 12 months the key endpoints and looking forward to feedback from the FDA as we focus on operationalizing the phase III trial and guiding to start that in the first half of next year.
Yep. I think that one of the other interesting things here is you talked about is you probably don't have to run as big of a study as some of the first gens. Can you walk through why some of those studies were so large and how you might be able to take advantage of the data so far to move faster?
Yeah. Those studies were designed before we had a true appreciation of the magnitude of the treatment effect on eGFR. They were really looking at the link between proteinuria reduction and eGFR benefit from the early phase II studies that provided proof of concept for the anti-APRIL mechanism. Those studies were really powered around something like a 2 ml per minute per year eGFR benefit relative to placebo control, which required these 500 to 600 patient studies that we've seen for the first gen agent. But what we've seen over time, both from extended follow-up on the phase II studies, but now phase III placebo-controlled eGFR data, is you do get this true eGFR stabilization relative to a 5 or 6 ml per minute eGFR decline in the placebo.
When you now design the study around those observed treatment effects, which are more than twice as large as originally predicted, you can get a much more efficient study design with a smaller sample size, even in the setting for us, where we do plan to take those two doses into phase III and compared to placebo. We think we'll have a 400 - 450 patient study, so smaller than those first gen programs, even with the two dosing intervals.
Great. Maybe last question before we move on from IgAN. I guess the size and the scope of this market obviously isn't lost on folks at this point. There's a lot of other programs in development in phase II and earlier stage. I guess, how do you see yourselves maintaining your position here among other next gen programs as well?
Yeah. It is a good question. Alex, we're not the only ones to notice.
Yeah.
This is a huge market, $20 billion opportunity, room for multiple entrants. Definitely, it's not going to be a winner take all. But we remain completely convinced that the selective anti-APRIL are going to be really the preferred dominant class. They do have the ability to produce Gd-IgA1, that pathogenic driver of disease, large reductions in proteinuria, and then, as Andrew's pointed out, stabilized kidney function. APRILs are really going to move to become foundational frontline therapy. And they do that without any unnecessary immunomodulation. So feel really good about the class, and then also about the profile of JADE101. Having those deepest IgA reductions to have the best clinical activity and do that with four injections a year is going to be really tough to displace for.
Yeah.
Anybody coming in behind us. There are agents coming, and we think that we'll have to keep watching them. There's another agent with a sweeper mechanism. We'll have to see, how does their phase I data translate into later trials? As mentioned, we think JADE101 is going to be very tough to beat in terms of those IgA reductions translating to proteinuria and the Q12-week dosing. We know there's other mechanisms coming behind as well.
Yeah.
Like CD38s, there's the IgA degraders. We think that those will have to show extremely compelling data to be able to dethrone the selective anti-APRILs from that foundational therapy. CD38 has a little bit of a broader effect on the immune system. Those have very frequent injections or IV, so not convenient for patients. With the IgA degraders, we just need to see more data, to see really where they end up. So feeling very positive about the positioning of JADE101 as a potential best-in-disease molecule.
Makes sense. Maybe let's pivot to JADE201. I guess, what got you excited about the BAFF receptor target and how is this differentiated from all the other types of B-cell depletion strategies out there right now?
Yeah. We are really excited about the dual mechanism of action of JADE201, a half-life extended afucosylated anti-BAFF receptor monoclonal antibody, because it addresses some limitations of the first-generation agents. Most of them are effective at depleting peripheral circulating B cells, through ADCC-like mechanisms in the systemic circulation, where there's a large number of effector cells, like NK cells are present. But they typically tend to be less effective at depleting tissue-based B cells, whether it's in the secondary lymphoid tissue, like the lymph node and spleen, or even in tertiary lymphoid structures that set up within target organs in autoimmune diseases that are really the autoreactive B cells that drive tissue injury. They're not as effective at depleting those, for two reasons. One is that there's not as many effector cells to use ADCC in those tissues. They're relatively sparse.
Secondly, when you deplete B cells, you get a large upregulation of the BAFF ligand as a compensatory response with the primary goal of repopulating the B-cell compartment. In other B-cell depleting strategies, that BAFF signal is left unopposed, so it leads to B-cell repopulation, and it can actually exacerbate autoreactivity, given that BAFF is considered an important driver of the underlying autoimmune condition. With JADE201, in that tissue setting and in that setting of high BAFF ligand upregulation, JADE201 binds the BAFF receptor and pharmacologically blocks it, so it starves it from that BAFF signal, providing tissue B-cell depletion, as well as blocking that compensatory response of BAFF upregulation in response to B-cell depletion.
We think that we can get better clinical activity across a variety of different systemic autoimmune diseases through this dual mechanism of action, depleting not only circulating B cells, but the tissue-resident B cells that are important in driving autoimmune disease.
You are running a phase I-B right now in RA patients. When you look at those data and think about where to go next, obviously ianalumab is being developed in a lot of different areas. How are you thinking about where you go with JADE201?
Yeah. As you mentioned, ianalumab has been in six different phase IIIs.
Yeah.
Different indications. We are looking really closely at those. They have positive Sjögren's data, ITP. Next year we will see lupus nephritis, and systemic sclerosis. All of those are potential candidates. Also there are other areas where Novartis likely did not go for strategic reasons.
Yeah.
That we think are good opportunities. We are going to characterize the drug out of our phase I, really understand that we think the key point out of the phase I is what is the duration of receptor occupancy. We saw in the ianalumab Sjögren's data, they had a Q4 and a Q12-week cohort where we think the Q4 week was almost fully covering the receptor to block in tissues like Andrew mentioned, not just the B-cell depletion in circulation. We want to see with JADE201 how long are we depleting or blocking that receptor. That will really guide for us what is the profile of this drug, and then where can we positively differentiate from ianalumab and then which indications are ones that we want to be for first in class.
More to come on that as we learn more about the profile of JADE201 and also about ianalumab's success in these other indications.
Great. Then maybe in the last few minutes here, you talked about JADE301 recently unveiled that program, interferon beta targeted for dermatomyositis. I guess what got you excited about that target and the data from dazukibart, and where do you see differentiation?
Yeah. Andrew, you want to cover that one?
Yeah. Really excited about the opportunity to provide a disease-modifying therapy in dermatomyositis, a debilitating skin and muscle autoimmune disease with strong evidence that IFN-β is an upstream driver of that entire pathogenesis and can be blocked selectively with a favorable safety profile to accompany that disease-modifying benefit. The phase II dazukibart data we think represents best-in-disease clinical proof of concept with a selective anti-IFN-β monoclonal antibody, not only on the total improvement score, which represents largely a muscle-based endpoint, but the skin disease, which is the hardest to treat aspect of dermatomyositis, and is a large unmet need despite the evolution of the treatment landscape there. Dazukibart provided really compelling benefit on CDASI, a measure of the skin severity index, in a very hard to treat moderate to severe dermatomyositis patient population. We do think IFN-β is the best mechanism to go after.
There are significant limitations with dazukibart. Most notably, it has low subQ bioavailability, so it needs to be administered at 600 mg IV every four weeks. The JADE301 design was focused on delivering an agent that could successfully transition to subQ dosing in this patient population, with optimized properties including improved potency, the YTE half-life extension with the goal of providing a convenient infrequent subQ administration of a disease-modifying therapy that's very targeted, with a favorable safety profile for chronic administration.
What's the status of JADE301?
We're on track to initiate a first-in-human study before the end of this year. Really excited to have three clinical programs on deck by the end of the year at Jade.
Great. You're going to share more preclinical data soon, right?
Exactly. I was just about to say that we have a presentation at the EADV.
Yeah.
Each weekend. We'll characterize the development candidate with more details on the profile in NHP versus dazukibart.
Great. Well, Tom, Andrew, always a pleasure. Thanks for joining us.
Great. Thanks so much.